Substituted fused heterocyclic C-glycosides

ABSTRACT

This invention relates to substituted fused heterocyclic C-glycosides, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of diabetes and Syndrome X.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional applications Ser. No.60/579,730, filed 15 Jun. 2004; Ser. No. 60/519,210, filed 12 Nov. 2003;Ser. No. 60/491,523, filed 1 Aug. 2003; and Ser. No. 60/491,534, filed 1Aug. 2003, each of which is incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to substituted fused heterocyclic C-glycosides,compositions containing them, and methods of using them, for example,for the treatment or prophylaxis of diabetes and Syndrome X.

BACKGROUND OF THE INVENTION

Diabetes is a chronic disorder affecting carbohydrate, fat and proteinmetabolism in animals.

Type I diabetes mellitus, which comprises approximately 10% of alldiabetes cases, was previously referred to as insulin-dependent diabetesmellitus (“IDDM”) or juvenile-onset diabetes. This disease ischaracterized by a progressive loss of insulin secretory function bybeta cells of the pancreas. This characteristic is also shared bynon-idiopathic, or “secondary”, diabetes having its origins inpancreatic disease. Type I diabetes mellitus is associated with thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

Type II diabetes mellitus (non-insulin-dependent diabetes mellitus orNIDDM) is a metabolic disorder involving the dysregulation of glucosemetabolism and impaired insulin sensitivity. Type II diabetes mellitususually develops in adulthood and is associated with the body'sinability to utilize or make sufficient insulin. In addition to theinsulin resistance observed in the target tissues, patients sufferingfrom type II diabetes mellitus have a relative insulin deficiency—thatis, patients have lower than predicted insulin levels for a given plasmaglucose concentration. Type II diabetes mellitus is characterized by thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

Syndrome X, also termed Insulin Resistance Syndrome (IRS), MetabolicSyndrome, or Metabolic Syndrome X, is recognized in some 2% ofdiagnostic coronary catheterizations. Often disabling, it presentssymptoms or risk factors for the development of Type II diabetesmellitus and cardiovascular disease, including impaired glucosetolerance (IGT), impaired fasting glucose (IFG), hyperinsulinemia,insulin resistance, dyslipidemia (e.g., high triglycerides, low HDL),hypertension and obesity.

Therapy for IDDM patients has consistently focused on administration ofexogenous insulin, which may be derived from various sources (e.g.,human, bovine, porcine insulin). The use of heterologous speciesmaterial gives rise to formation of anti-insulin antibodies which haveactivity-limiting effects and result in progressive requirements forlarger doses in order to achieve desired hypoglycemic effects.

Typical treatment of Type II diabetes mellitus focuses on maintainingthe blood glucose level as near to normal as possible with lifestylemodification relating to diet and exercise, and when necessary, thetreatment with anti-diabetic agents, insulin or a combination thereof.NIDDM that cannot be controlled by dietary management is treated withoral antidiabetic agents.

Although insulin resistance is not always treated in all Syndrome Xpatients, those who exhibit a prediabetic state (e.g., IGT, IFG), wherefasting glucose levels may be higher than normal but not at the diabetesdiagnostic criterion, is treated in some countries (e.g., Germany) withmefformin to prevent diabetes. The anti-diabetic agents may be combinedwith pharmacological agents for the treatment of the concomitantco-morbidities (e.g., antihypertensives for hypertension, hypolipidemicagents for lipidemia).

First-line therapies typically include mefformin and sulfonylureas aswell as thiazolidinediones. Mefformin monotherapy is a first linechoice, particularly for treating type II diabetic patients who are alsoobese and/or dyslipidemic. Lack of an appropriate response to metforminis often followed by treatment with metformin in combination withsulfonylureas, thiazolidinediones, or insulin. Sulfonylurea monotherapy(including all generations of drugs) is also a common first linetreatment option. Another first line therapy choice may bethiazolidinediones. Alpha glucosidase inhibitors are also used as firstand second line therapies. Patients who do not respond appropriately tooral anti-diabetic monotherapy, are given combinations of theabove-mentioned agents. When glycemic control cannot be maintained withoral antidiabetics alone, insulin therapy is used either as amonotherapy, or in combination with oral antidiabetic agents.

One recent development in treating hyperglycemia is focused on excretionof excessive glucose directly into urine. Specific inhibitors of SGLTshave been shown to increase the excretion of glucose in urine and lowerblood glucose levels in rodent models of IDDM and NIDDM.

SUMMARY OF THE INVENTION

One aspect of the present invention is directed to methods andcompositions for the treatment or prophylaxis of diabetes, Syndrome X,or associated symptoms or complications. More specifically, thisinvention is directed to a novel method of treating diabetes or SyndromeX, or associated symptoms or complications thereof, in a subjectafflicted with such a condition, said method comprising administeringone or more glucose reabsorption inhibitors and administering one ormore antidiabetic agent(s) for the treatment of diabetes or Syndrome X,or associated symptoms or complications thereof.

Another aspect of the invention features compounds of formula (IV)

wherein:one of the dashed lines between NR₁ and X or between X and Y is present,or both are absent;two of V, M, and W are H and the third is

R₁ is H, or C₁₋₄ alkyl; or R₁ is absent where the dashed line betweenNR¹ and X is present, X is N, C═O, CH, or C-Q-Z;Y is N-Q-Z or C-Q-Z, where X is N, C═O, or CH;Y is CH, where X is C-Q-Z;Q=—(CH₂)_(n)— where n=1 or 2;Z is substituted or unsubstituted, and is selected from C₃₋₇ cycloalkyl,phenyl, a 5- or 6-membered heteroaryl having 1 or 2 heteroatomsindependently selected from N, O, and S, a biaryl, a 9- or 10-memberedfused bicyclyl (such as naphthyl), and a fused heterobicyclyl, whereinsaid fused heterobicyclyl has between 1 and 4 heteroatoms (andpreferably between 1 and 3 or between 1 and 2 heteroatoms) independentlyselected from N, O, and S;P═H, C₁₋₇ acyl, or (C₁₋₆ alkoxy)carbonyl;or a pharmaceutically acceptable salt, thereof.

One aspect of the invention features a pharmaceutical compositioncomprising a glucose reabsorption inhibitor, at least one additionalantidiabetic agent, and a pharmaceutically acceptable carrier. Theinvention also provides a process for formulating a pharmaceuticalcomposition, comprising formulating together a glucose reabsorptioninhibitor, one or more antidiabetic agent(s), and a pharmaceuticallyacceptable carrier.

An embodiment of the invention is a method for treating diabetes orSyndrome X, or associated symptoms or complications thereof in asubject, said method comprising administering to said subject a jointlyeffective amount of a glucose reabsorption inhibitor and administeringto said subject a jointly effective amount of at least one antidiabeticagent, said combined administration providing the desired therapeuticeffect.

Another embodiment of the invention is a method for inhibiting the onsetof diabetes or Syndrome X, or associated symptoms or complicationsthereof in a subject, said method comprising administering to saidsubject a jointly effective dose of a glucose reabsorption inhibitor andadministering to said subject a jointly effective amount of one or moreanti-diabetic agent(s), said combined administration providing thedesired prophylactic effect.

In the disclosed methods, the diabetes or Syndrome X, or associatedsymptoms or complications thereof, is selected from IDDM, NIDDM, IGT,IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis,polycystic ovarian syndrome, hypertension, ischemia, stroke, heartdisease, irritable bowel disorder, inflammation, and cataracts.

Also included in the invention is the use of one or more glucosereabsorption inhibitors in combination with one or more antidiabeticagents for the preparation of a medicament for treating a conditionselected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy,retinopathy, atherosclerosis, polycystic ovarian syndrome or polycysticovarian syndrome, hypertension, ischemia, stroke, heart disease,irritable bowel disorder, inflammation, and cataracts.

DETAILED DESCRIPTION OF THE INVENTION

All diabetics, regardless of their genetic and environmentalbackgrounds, have in common an apparent lack of insulin or inadequateinsulin function. Because transfer of glucose from the blood into muscleand fatty tissue is insulin dependent, diabetics lack the ability toutilize glucose adequately, which leads to undesired accumulation ofglucose in the blood (hyperglycemia). Chronic hyperglycemia leads todecrease in insulin secretion and contributes to increased insulinresistance, and as a result, the blood glucose concentration isincreased so that diabetes is self-exacerbated (Diabetologia, 1985,“Hyperglycaemia as an inducer as well as a consequence of impaired islecell function and insulin resistance: implications for the management ofdiabetes”, Vol. 28, p. 119); Diabetes Cares, 1990, Vol. 13, No. 6,“Glucose Toxicity”, pp. 610-630). Therefore, by treating hyperglycemia,the aforementioned self-exacerbating cycle is interrupted so that theprophylaxis or treatment of diabetes is made possible.

U.S. Pat. No. 6,153,632 to R. Rieveley discloses a method andcomposition stated to be for the treatment of diabetes mellitus (Type I,Impaired Glucose Tolerance [“IGT”] and Type II), which incorporates atherapeutic amount of one or more insulin sensitizers along with one ormore of an orally ingested insulin, an injected insulin, a sulfonylurea,a biguanide or an alpha-glucosidase inhibitor for the treatment ofdiabetes mellitus.

According to one aspect, the invention features the combination of aPPAR modulator, preferably a PPAR δ agonist, and an SGLT inhibitor,preferably an SGLT 2 inhibitor or a selective SGLT 2 inhibitor.

Terms

Some terms are defined below and by their usage throughout thisdisclosure.

Unless otherwise noted, “alkyl” and “alkoxy” as used herein, whetherused alone or as part of a substituent group, include straight, cyclic,and branched-chain alkyl having 1 to 8 carbon atoms, or any numberwithin this range. For example, alkyl radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 2-butenyl,2-butynyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl,neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals areoxygen ethers formed from the previously described straight or branchedchain alkyl groups. The alkyl and alkoxy group may be independentlysubstituted with one to five, preferably one to three groups selectedfrom halogen (F, Cl, Br, I), oxo, OH, amino, carboxyl, and alkoxy. Thealkyl and alkoxy group may also be independently linked to one or morePEG radicals (polyethylene glycol).

The term “acyl” as used herein, whether used alone or as part of asubstituent group, means an organic radical having a carbonyl grouplinked to hydrocarbyl group having 1 to 7 carbon atoms (branched orstraight chain or cyclic) derived from an organic acid by removal of thehydroxyl group. For example C₄ acyl can include (CO)CH₂CH₂CH₂CH₃ and(CO)(CH₂ (CH) (CH₃)₂; similarly, C₆ acyl includes both (CO)(C₆H₁₃) and(CO)(C₆H₅). The term “Ac” as used herein, whether used alone or as partof a substituent group, means acetyl.

“Aryl” is a carbocyclic aromatic radical including, but not limited to,phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radicalmay be substituted by independent replacement of 1 to 3 of the hydrogenatoms thereon with halogen, OH, CN, mercapto, nitro, amino, cyano,optionally substituted C₁-C₈-alkyl, optionally substituted alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—. Illustrative aryl radicals include, for example, phenyl,naphthyl, biphenyl, indene

indane

fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl,carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl,hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl,acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph”or “PH” denotes phenyl.

The term “heteroaryl” as used herein represents a stable five orsix-membered monocyclic or bicyclic aromatic ring system which consistsof carbon atoms and from one to three heteroatoms selected from N, O andS. The heteroaryl group may be attached at any heteroatom or carbonatom, which results in the creation of a stable structure. Examples ofheteroaryl groups include, but are not limited to benzofuranyl,benzothiophenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl,benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl or quinolinyl. Prefered heteroaryl groups includepyridinyl, thiophenyl, furanyl, and quinolinyl. When the heteroarylgroup is substituted, the heteroaryl group may have one to threesubstituents which are independently selected from halogen, OH, CN,mercapto, nitro, amino, cyano, optionally substituted C₁-C₈-alkyl,optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkyl-amino, di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

The terms “heterocycle,” “heterocyclic,” and “heterocyclyl” refer to anoptionally substituted, fully or partially saturated, aromatic ornonaromatic, cyclic group which is, for example, a 4- to 7-memberedmonocyclic, 7- to 11-membered (or 9- to 10-membered) bicyclic (orheterobicyclyl), or 10- to 15-membered tricyclic ring system, which hasat least one heteroatom in at least one carbon atom containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, andsulfur atoms, where the nitrogen and sulfur heteroatoms may alsooptionally be oxidized. The nitrogen atoms may optionally bequaternized. The heterocyclic group may be attached at any heteroatom orcarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl;pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl;isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl;piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl;2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl;tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl;thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone;1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplarybicyclic heterocyclic groups (or heterobicyclyls) include quinuclidinyl;tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl;dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone;dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl;benzimidazolyl, benzthiazolyl; piperonyl; tetrahydroquinolinyl; and thelike. When the heteroaryl group is substituted, the heterocyclyl may beindependently substituted with one to five, preferably one to threegroups selected from halogen, OH, CN, mercapto, nitro, amino, cyano,optionally substituted C₁-C₈-alkyl, optionally substituted alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

The term “biaryl” includes a heteroaryl linked to a phenyl, a phenyllinked to a heteroaryl (such as furan, pyridine, thiophene), and aphenyl linked to a phenyl. Examples of phenyl-phenyl, heteroaryl-phenyland phenyl-heteroaryl, include:

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “combined administration” includes co-administrationwherein: 1) the two or more agents are administered to a subject atsubstantially similar times; and 2) the two or more agents areadministered to a subject at different times, at independent intervalswhich may or may not overlap or coincide.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is the object of treatment,observation or experiment.

The term “RXR modulator” as used herein, refers to Retinoid-X receptoragonists, partial agonists, or antagonists. Preferably the modulatorincreases insulin sensitivity. According to one aspect, the modulator isan RXR agonist.

Diabetes, Syndrome X, and associated symptoms or complications includesuch conditions as IDDM, NIDDM, IGT, IFG, obesity, nephropathy,neuropathy, retinopathy, atherosclerosis, polycystic ovarian syndrome,hypertension, ischemia, stroke, heart disease, irritable bowel disorder,inflammation, and cataracts. Examples of a prediabetic state includesIGT and IFG.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated by the modulation of glucosereabsorption activity or other antidiabetic agent activity or both.Thus, the present invention provides combinations of two or more drugswherein, for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

The term “protecting groups” refer to those moieties known in the artthat are used to mask functional groups; protecting groups may beremoved during subsequent synthetic transformations or by metabolic orother in vivo administration conditions. During any of the processes forpreparation of the compounds of the present invention, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973;and T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, 1999. The protecting groupsmay be removed at a convenient subsequent stage using methods known inthe art. Examples of hydroxyl and diol protecting groups are providedbelow.

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, and polyethyleneglycol ethers.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(/midazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p -xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate), and polyethyleneglycol esters.

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, methyldithiocarbonate, and polyethyleneglycol carbonates.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Protection for 1,2- and 1,3-Diols

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl Derivatives

Examples of silyl derivatives include di-t-butylsilylene group, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

Glucose Reabsorption Inhibitors

One method of treating hyperglycemia is to excrete excessive glucosedirectly into urine so that the blood glucose concentration isnormalized. For example, sodium-glucose cotransporters (SGLTs),primarily found in chorionic membrane of the intestine and the kidney,are a family of proteins actively involved in the normal process ofglucose absorption. Among them, SGLT1 is present in intestinal and renalepithelial cells (Lee et al., 1994), whereas SGLT2 is found in theepithelium of the kidney (You et al., 1995, MacKenzie et al., 1994).Glucose absorption in the intestine is primarily mediated by SGLT1, ahigh-affinity low-capacity transporter with a Na⁺:glucose transportratio of 2:1. SGLT2, also known as SAAT1, transports Na⁺ and glucose ata ratio of 1:1 and functions as a low-affinity high-capacitytransporter. These SGLTs are characterized in Table 1: TABLE 1 PreferredK_(m) * TmG ** K_(m) * ISOFORM TISSUE Stoichiometry Substrate in vitroin vitro In vivo SGLT1 Sm. Intestine 2:1 D-glucose 0.1 nd Nd D-galactoseKidney (S1, S3) 2:1 D-glucose 0.39 7.9 0.3 D-galactose SGLT2 Kidney (S3)1:1 D-glucose 1.64 83 6 (SAAT1)* (mM) for D-glucose** Maximal transport rate pmol/min/mm

1. Renal reabsorption of glucose is mediated by SGLT1 and SGLT2(Silverman et al., 1992; Deetjen et al., 1995). Plasma glucose isfiltered in the glomerulus and is transepithelially reabsorbed in theproximal tubules. SGLT1 and SGLT2 are located in the apical plasmamembranes of the epithelium and derive their energy from the inwardsodium gradient created by the Na⁺/K⁺ ATPase pumps located on thebasolateral membrane. Once reabsorbed, the elevated cytosolic glucose isthen transported to the interstitial space by facilitated glucosetransports (GLUT1 and GLUT2). Therefore, inhibition of SGLTs reducesplasma glucose through suppression of glucose reabsorption in thekidney. A therapeutically or prophylactically effective amount of anSGLT inhibitor, such as that sufficient to increase urine glucoseexcretion, or to decrease plasma glucose, in a subject by a desiredamount per day, can be readily determined using methods established inthe art. Recently, it has been found that phlorizin, a natural glycosidepresent in barks and stems of Rosaceae (e.g., apple, pear, etc.),inhibits Na⁺-glucose co-transporters located in chorionic membrane ofthe intestine and the kidney. By inhibiting Na⁺-glucose co-transporteractivity, phlorizin inhibits the renal tubular glucose reabsorption andpromotes the excretion of glucose so that the glucose level in a plasmais controlled at a normal level for a long time via subcutaneous dailyadministration (Journal of Clinical Investigation, 1987, Vol. 79, p.1510).

Other SGLT inhibitors include alkyl- and phenyl-glucosides,1-5-isoquinolinesulfonyl)-2-methylpiperazine-HCl (indirectly via proteinkinase C), p-chloromercuribenzoate (PCMB), N,N′-dicyclohexylcarbodiimide(DCCD), copper and cadmium ions, and trivalent lanthanides.

Compounds

The invention features compounds of Formula (IV):

wherein:one of the dashed lines between NR₁ and X or between X and Y is present,or both are absent;two of V, M, and W are H and the third is

R₁ is H, or C₁₋₄ alkyl; or R₁ is absent where the dashed line betweenNR¹ and X is present,X is N, C═O, CH, or C-Q-Z;Y is N-Q-Z or C-Q-Z, where X is N, C═O, or CH;Y is CH, where X is C-Q-Z;Q=—(CH₂)_(n)— where n=1 or 2;Z is substituted or unsubstituted, and is selected from C₃₋₇ cycloalkyl,phenyl, a 5- or 6-membered heteroaryl having 1 or 2 heteroatomsindependently selected from N, O, and S, a biaryl-, a 9- or 10-memberedfused bicyclyl (such as naphthyl), and a fused heterobicyclyl, whereinsaid fused heterobicyclyl has between 1 and 4 heteroatoms (andpreferably between 1 and 3 or between 1 and 2 heteroatoms) independentlyselected from N, O, and S;P═H, C₁₋₇ acyl, or (C₁₋₆ alkoxy)carbonyl;or a pharmaceutically acceptable salt, thereof.

Examples of preferred compounds of Formula (IV) include: (a) R₁ is H orabsent; (b) Z is independently substituted with between 1 and 3substituents independently selected from C₁₋₄ alkoxy, phenoxy, C₁₋₄alkyl, C₃₋₆ cycloalkyl, halo, hydroxy, cyano, amino, C₁₋₄ alkylthio,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl, C₁₋₄-aminoalkyl, mono and diC₁₋₄ alkylamino, phenyl, C₁₋₄ alkylaminosulfonyl (SO₂NHR), amino(C₁₋₄alkylsulfonyl) (NHSO₂R), di C₁₋₄ alkylaminosulfinyl (SONHRR), C₁₋₄alkylamido (NHCOR), C₁₋₄ alkylcarbamido (CONHR), 5-6 memberedheterocyclyl containing between 1 and 3 heteroatoms independentlyselected from N, S, and O; and wherein the substituent(s) on Z can befurther independently substituted with between 1 and 3 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ alkyl, halo, hydroxy,cyano, amino, mono or di C₁₋₄ alkyl amino and C₁₋₄ alkylthio; (c) Z is4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substitutedor unsubstituted thienyl, biaryl, benzofuranyl, dihydrobenzofuranyl,4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl,indanyl, naphthyl, and 2,3-dihydro-benzo[1,4]dioxan; (d) limitations of(c) wherein Z is unsubstituted or substituted with between 1 and 2substituents independently selected from methoxy, ethoxy, fluoro,chloro, methyl, ethyl, propyl, butyl and isopropyl; (e) Z is biphenyl,4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl, 4-(1H-pyrazol-1-yl)-phenyl,(4-ethyl)phenyl, (4-propyl)phenyl, (4-methoxy)phenyl,dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl; (f) R₁ is H; (g) n is1; (h) R₁ is H or absent, and n is 1; (i) Z is biphenyl,4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl, 4-(1H-imidazole-1-yl)-phenyl,4-(1H-pyrazol-1-yl)-phenyl, (4-ethyl)phenyl, (4-propyl)phenyl,(4-methoxy)phenyl, dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl;and Z is unsubstituted or substituted with between 1 and 2 substituentsindependently selected from methoxy, ethoxy, fluoro, chloro, methyl,ethyl, propyl, butyl and isopropyl; (j) limitations of (i) and R₁ is H;(k) limitations of (i) and n is 1; (l) W and M are H; (m) V and M are H;(n) X is CH and Y is C-Q-Z; (O) X is C-Q-Z and Y is CH; (p) andcombinations of the above.

Preferred examples of compounds of the invention include:3-(4-Ethylbenzyl)-5-(β-D-glucopyranosyl)-1H-indole;5-(β-D-Glucopyranosyl)-3-(4-methoxybenzyl)-1H-indole;5-(β-D-Glucopyranosyl)-3-[2-(4-methoxyphenyl)-ethyl]-1H-indole; and3-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-1H-indole.

Additional preferred compounds include those selected from2-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-1H-indole;3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-5-(β-D-glucopyranosyl)-1H-indole;5-(β-D-Glucopyranosyl)-3-(5-ethyl-2-thienyl)-1H-indole;3-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-3H-benzimidazole;3-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-1,3-dihydro-benzoimidazol-2-oneand 3-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-3H-benzotriazole.

The most preferred compounds are selected from:3-(4-Ethylbenzyl)-5-(β-D-glucopyranosyl)-1H-indole;2-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-1H-indole;5-(β-D-Glucopyranosyl)-3-(5-methyl-2-thienyl)-1H-indole;3-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-3H-benzimidazole and3-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-3H-benzotriazole.

C. SYNTHETIC METHODS

One aspect of the invention features compounds of formula (IV). Thesecompounds can be made according to traditional synthetic organic methodsor combinatorial or matrix synthesis methods. The following schemes andchemical Examples 1-4 provide general guidance.

Compounds of this invention where X is C—H, Y is C-Q-Z (e.g. 3-alkylindole) can be prepared as outlined in Scheme 1. Compounds of formula 1wherein R₃ is H and P₁ is N,N-diethylcarbamyl can be prepared bytreatment of the sodium salt of commercially available5-bromo-1H-indole-3-carboxaldehyde with N,N-diethylcarbamyl chloride inanhydrous THF. The protected indole may be treated with ylides understandard Wittig reaction conditions to provide an E/Z mixture ofcompounds. Hydrogenation of the alkene over Platinum(IV)oxide (Adam'scatalyst) in a chlorinated solvent at 1 atmosphere provides compounds offormula 2, wherein n is 2. A compound of formula 1 can also be treatedwith an aryl magnesium bromide in THF to give an indolecarbinol. Thecrude indolecarbinol can be reduced with triethylsilane and stannicchloride in dichloromethane at −78° C. to provide compounds of formula2, wherein n is 1. The indole nitrogen of compounds of formula 2, wheren is 1 or 2, can be deprotected by treatment with an aqueous base suchas sodium hydroxide in refluxing ethanol to remove theN,N-diethylcarbamyl group followed by reprotection withtert-butlydimethylsilyl (TBDMS) group (P₂) by treatment withtert-butyldimethylsilyl chloride using known procedures to yield 5-bromoindole derivative 5.

Alternatively, a compound of formula 5, where n is 1 (either4-bromoindole derivatives or 5-bromoindole or 6-bromoindolederivatives), can be prepared in three steps from commercial availablesources of formula 3. Friedel-Craft acylation of compounds of formula 3with substituted benzoyl chlorides using a Lewis Acid, such as aluminumtrichloride, in a chlorinated solvent, such as dichloromethane, followedby reduction of the carbonyl group with sodium borohydride to providecompounds of formula 4. The indole nitrogen of formula 4 can beprotected with TBDMS group as described above to give compounds offormula 5, where n is 1.

Compounds of formula 5 are activated for coupling by treatment witht-BuLi at −78° C. in a solvent such as THF prior to addition of2,3,4,6-tetra-O-benzyl-β-D-glucolactone as described by Czernecki andVille [J. Org. Chem. 1989, 53, 610-612]. The resulting lactol can betreated with silanes such as triethylsilane in a solvent such asdichloromethane at −30° C. to provide compounds of formula 6. The TBDMSgroup can be removed with an aqueous base such as sodium hydroxide inrefluxing THF to yield compounds of formula 7. Hydrogenolysis ofglucopyranose 7 over palladium hydroxide (Pearlman's catalyst) at oneatmosphere can provide compounds of formula 8 where P is H.

The sodium salt of 7 can be treated with an alkyl halide to give theN-alkylated (R₁) product 9, which was undergone hydrogenolysis aspreviously described to provide compound of formula 10 where P is H.

Further treatment of compounds of formula 8 or 10, where P is H, withone equivalent of alkyl chloroformate or alkanoyl chloride in collidineto selectively acylate the 6-OH group of the glucopyranose can providecompounds of formula 8 or 10, where P is acyl, or alkoxycarbonyl.

Compounds of this invention wherein Y is N-Q-Z, X is N, C═O or C—H, andR₁ is as defined in the claims above could be prepared as outlined inScheme 2 using procedures known in the art for the synthetictransformations described. Commercially availableN-(2-Bromo-6-nitro-phenyl)-acetamide could be heated under acidiccondition to remove the acetyl group then alkylated with substitutedbenzyl, aryl or heteroaryl alkyl halides, acylated with benzoyl orphenylacetyl chlorides followed by LAH or borane reduction orreductively aminated with substituted benzaldehydes in the presence ofsodium cyanoborohydride to provide compounds of formula 9. The nitrogroup could then be reduced using reagents such as tin (II) chloride oriron in acetic acid to obtain compounds of formula 11 wherein thebromine is attached at position V in claim 1.

Alternatively, one could start with commercially available4-Bromo-2-nitroaniline, introduce the side-chain containing Z asdescribed above to afford compounds of formula 10 where R′ is—(CH₂)_(n)Z then reduce the nitro group to provide compounds of formula11 wherein the bromine is attached at position M in claim 1.

On the other hand, the aniline nitrogen of commercially available4-Bromo-2-nitroaniline could be acetylated or alternatively protectedwith an appropriate protecting group such as toluenesulfonyl orbenzenesulfonyl to yield compounds of formula 10 wherein R′ is theprotecting group. The nitro group could then be reduced to a primaryamine with tin (II) chloride and subsequently alkylated by treatmentwith substituted benzyl, aryl or heteroaryl alkyl halides, under basicconditions or reductively aminated with substituted benzaldehydes in thepresence of sodium cyanoborohydride. Alternatively the primary aminecould be acylated with benzoyl or phenylacetyl chlorides followed by LAHor borane reduction. Final removal of the nitrogen protecting groupusing procedures known in the art could provide compounds of formula 11wherein the bromine is attached at position W in claim 1.

Compounds of formula 11 could be reacted further to form compounds offormula 12, 13, and 14. These transformations can be accomplished bytreating the diamine with 1,1′-thiocarbonyldiimidazole or carbondisulfide to provide compound of formula 12 or with triphosgene, urea orcarbonyldimidazole to give compounds of formula 13. Alternatively, thediamine 11 could be treated with sodium nitrate under acidic conditionsat cool temperatures to provide compounds of Formula 14.

Methylation of compounds of formula 12 with iodomethane in the presenceof a base can afford compounds of formula 16. Compounds of formula 13can be treated with base such as sodium hydride and alkylated with alkylhalides to provide compounds of formula 17 wherein R₁ is alkyl. Theunsubstituted nitrogen of compound of formula 13 can also be protectedwith an alkoxy carbonyl group as described by Meanwell et. al. [J. Org.Chem. 1995, 60, 1565-1582] to provide compounds of formula 17 wherein R₁is either an ethoxy carbonyl moiety or a t-butoxycarbonyl group.

Formation of the C-glycosides can be accomplished by treating compoundsof formula 14, 16 or 17 (compound 15 is omitted) with butyllithium at−78° C. prior to the addition of 2,3,4,6-tetra-O-benzyl-β-D-glucolactonefollowed by reduction of the resulting hemiacetal in the presence ofexcess triethylsilane and boron trifluoride diethyl etherate in anappropriate solvent such as dichloromethane as described by Czerneckiand Ville (J. Org. Chem. 1989, 54, 610-612). Compounds of formula 18,wherein R₁ is H, can be prepared by removing the protection groups underbasic condition (for ethoxy carbonyl group) or under acidic condition(for tert-butoxycarbonyl group) followed by debenzylation of thehydroxyl groups using palladium catalysts under hydrogenationconditions. Compounds of formula 18, wherein R1 is an alkyl group, orformula 19 can be formed by debenzylation of the hydroxyl groups usingpalladium catalysts under hydrogenation conditions. Compounds of formula20 wherein R₃ is H can be prepared by a Raney nickel mediated cleavageof the 2-methylthio group as described by Townsend, et. al. (J. Med.Chem. 1994, 37, 2942-2949) followed by debenzylation of the hydroxylgroups using palladium catalysts under hydrogenation conditions.

Further treatment with one equivalent of alkyl chloroformate or alkanoylchloride in collidine to selectively acylate the 6-OH group of theglucopyranose can provide compounds of formula 21 where P is acyl, oralkoxycarbonyl.

Compounds of this invention where X is C-Q-Z and Y is CH (e.g. 2-alkylindole) as defined in the claims above can be prepared as outlined inScheme 3. Compounds of formula 22 can be prepared by treatment of thesodium salt of commercially available bromoindoles (either 4-bromoindoleor 5-bromoindole or 6-bromoindole) with an alkyl halides in anhydrousTHF. The resulting N-alkyl indole can be rearranged to 2-alkyl indole at180° C. in polyphosphoric acid under microwave condition, followed byprotection of indole nitrogen with TBDMS group (P₂) to provide compoundsof formula 23.

Formation of the C-glycosides can be accomplished by treating compoundsof formula 23 with butyllithium at −78° C. prior to the addition of2,3,4,6-tetra-O-benzyl-β-D-glucolactone as described in Scheme 1. Theresulting lactol can be treated with silanes, such as triethylsilane, ina solvent such as dichloromethane at −30° C., followed by deprotectionof the TBDMS group with an aqueous base, such as sodium hydroxide, inrefluxing THF to yield compounds of formula 24.

Hydrogenolysis of glucopyranose 24 over palladium hydroxide (Pearlman'scatalyst) at one atmosphere can provide compounds of formula 25 where Pis H. The sodium salt of 24 can be treated with an alkyl halide to givethe N-alkylated (R₁) product 26, followed by hydrogenolysis aspreviously described to provide compound of formula 27 where P is H.

D. ADDITIONAL ANTIDIABETIC AGENTS

Antidiabetic agents that can be used according to the invention, as asecond, third, or subsequent antidiabetic agent, in a composition,formulation, or combination method of treatment (dosing regimen)include, but are not limited to the classes and compounds exemplified inTable 2. TABLE 2 Combination Therapies with SGLT Inhibitors Mechanism orClass Drug/Compound Biguanide (class) metformin Fortamet (metformin XT)metformin GR metformin XL NN-414 fenofibrate/metformin combo InsulinSecretagogue glimeparide (mech), Sulfonylureas glyburide/glibenclamidecombo (class) glyburide/metformin combo glipizide glipizide/metformincombo gliclazide chlorpropamide tolbutamide tolazamide InsulinSecretagogue repaglinide (mech), Meglitinides nateglinide (class)mitiglinide Alpha-glucosidase acarbose inhibitors (mech) miglitolvoglibose emiglitate Insulin and Insulin insulin lispro analogues(class) insulin glargine insulin detemir insulin glulisine insulinaspart human insulin (Humulin R) human insulin (Novolin R human insulin(Novolin BR) insulin, zinc suspension (Humulin L) insulin NHP (HumulinN) insulin, zinc suspension (Novolin L) insulin NHP (Novolin N) insulin,zinc suspension (Humulin U) human insulin, regular and NHP mix (Humulin50/50) human insulin, regular and NHP mix (Humulin 70/30) human insulin,regular and NHP mix (Novolin 70/30) Inhaled insulin (class) Exubera AERxInsulin Diabetes Management System AIR inhaled insulin Oral insulin(class) Oralin PPARgamma (mech) rosiglitazone rosiglitazone/metformincombo pioglitazone isaglitazone (netoglitazone, MCC-555)rosiglitazone/sulfonylurea ragaglitazar balaglitazone (NN-2344) R-483rivoglitazone (CS-011) FK-614 SCD-DKY tesaglitazar T131 CLX0921LY-293111 (VML-295) MBX 102 AA10090 CDDO (TP-155C) DRF-2189 PHT-46farglitazar GW-7845 L-764406 NC-2100 PN 2022 (PN 2034) PPARalpha/gammadual MK767/MK0767 (KRP 297) agonists (mech) muraglitazar (BMS-298585)tesaglitazar LY-818 oxeglitazar (EML-4156) LY-929 BVT-142 DRF-2655DRF-4832 DRF-4158 LY-465608 KT6-207 LSN-862 PPARalpha Agonist (mech)Fenofibrate Gemfibrozil Clofibrate Ciprofibrate Benzafibrate K-111LY518674 (LY674) KRP-101 NS-220 GW-9578 GW-7647 GW-9820 LF-200337ST-1929 Wy-14643 PPARdelta Agonist (mech) GW501516 GW-1514 L-165041 GW8547 PPARalpha/delta Dual GW-2433 Agonist (mech) PPARgamma/delta Dualnone in the last PPAR CEA Agonist (mech) PPARalpha/gamma/delta CLX-0940Modulator (mech) RXR Agonist (mech) Insulin Seretagogue Exanatideinjectable (mech), GLP-1 analogue Exanatide LAR injectable (class)Exanantide oral Liraglutide GLP-1 agonist (mech) exenatide (AC2993)liraglutide (NN2211) LY-307161 CJC-113 ZP10 GLP-1 BIM-51077 DPPIVInhibitor (mech) LAF-237 P32/98 P93/01 NVP-728 Lipase Inhibitor (mech)Orlistat ATL962 Glucokinase Activator (mech) Ro 28-1675 Ro 27-4375beta-3 Agonist (mech) LY-337604 L-796568 CP-331684 CP-331679 CP-114271Rafabegron (TAK-677) YM-178 N5984 GW427353 IBAT Inhibitor (mech)AZD-7806 SC-990 SC-017 GW-264 HM74a/HM74 Agonist (mech) AcipimoxGlucocorticoid A348441 Antagonist (mech) A362947 CP394531 CP409069CP472555 Glycogen Phosphorylase a NN4201 Inhibitor (mech) Ingliforib(CP368296) FXR Antagonist (mech) GW-4064 LXR Agonist (mech) GW-3965T-0901317 T-0314407 FXR Antagonist (mech) GLP-1 Analogue (class) AlbugonGSK-3beta Inhibitor (mech) PTP-1b Inhibitor (mech) ISIS-113715 KP102Amylin Receptor Agonist Pramlintide (symlin/amylin) NO Scavenger (mech)NOX-700 11beta-Hydroxysteroid BVT-3498 Dehydrogenase Inhibitor PeptideYY hormone AC162325 Glucagon Antagonist (mech) NN-2501 PEPCK Inhibitor(mech) R1438 Somatotropin Release- SOM230 inhibiting Factor (mech) CPT-1Inhibitor (mech) ST1326 Carboxypeptidase MLN-4760 Inhibitor (mech)Leptin analogue (class) Metrileptin

E. COMBINATIONS

The invention features a combination therapy comprising administering aglucose reabsorption inhibitor, such as an SGLT inhibitor, and one ormore antidiabetic agent(s) for the treatment of diabetes or Syndrome X,or associated symptoms or complications thereof. The demonstratedefficacy of SGLT inhibitors in numerous models of NIDDM validates theutility of this drug alone for the treatment of NIDDM in humans. Sinceglucose reabsorption inhibitors have a mechanism of action distinct fromthat of other antidiabetic agents, such as RXR modulators, the disclosedcombination may have the advantage of reducing the amount of either drugnecessary to achieve combined therapeutic or pharmaceutical efficacy,relative to the use of either drug alone, thereby reducing one or moreadverse side-effects, which often include weight gain, edema, cardiachypertrophy, hepatohypertrophy, hypoglycemia, or hepatotoxicity, or anycombination thereof.

The invention provides a method for treating diabetes or Syndrome X, orcomplications thereof in a subject, said method comprising administeringto said subject a jointly effective amount of a glucose reabsorptioninhibitor in combination with a jointly effective amount of anantidiabetic agent, such as an RXR modulator. In one aspect of theinvention, the antidiabetic agent is an RXR agonist or RXR antagonistthat increases insulin sensitivity in the subject. For example, aninsulin sensitizer can increase glucose tolerance in a subject in anoral glucose tolerance test.

Preferably, the diabetes or Syndrome X, or associated symptoms orcomplication thereof is selected from IDDM, NIDDM, IGT, and IFG.

This invention also provides a pharmaceutical composition comprising oneor more glucose reabsorption inhibitors (alone or in combination withone or more antidiabetic agents), and a pharmaceutically acceptablecarrier. In one aspect of the invention, the antidiabetic agent is anRXR agonist or RXR antagonist that increases insulin sensitivity in thesubject.

In particular, the glucose reabsorption inhibitor is a SGLT1 and/orSGLT2 inhibitor.

For use in medicine, the salt or salts of the compounds of Formula (IV)refer to non-toxic “pharmaceutically acceptable salt or salts.” Othersalts may, however, be useful in the preparation of compounds accordingto this invention or of their pharmaceutically acceptable salts.Representative organic or inorganic acids include, but are not limitedto, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric,phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic,fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representativebasic/cationic salts include, but are not limited to, benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, orzinc. The compounds of Formula (IV) or a pharmaceutically acceptablesalt thereof, may include an intramolecular salt thereof, or a solvateor hydrate thereof.

F. ADMINISTRATION, FORMULATION, and DOSAGES

The utility of the disclosed compounds, compositions, and combinationsto treat disorders in glucose and lipid metabolism can be determinedaccording to the procedures well known in the art (see the referenceslisted below), as well as all the procedures described in U.S. Pat. Nos.5,424,406, 5,731,292, 5,767,094, 5,830,873, 6,048,842, WO01/16122 andWO01/16123 which are incorporated herein by reference. The compound maybe administered to a patient by any conventional route ofadministration, including, but not limited to, intravenous, oral,subcutaneous, intramuscular, intradermal and parenteral administration.Preferably, formulations are for oral administration.

The present invention also provides pharmaceutical compositionscomprising one or more glucose reabsorption inhibitors and one or moreRXR modulators in association with a pharmaceutically acceptablecarrier.

The daily dosage of the products may be varied over a wide range from 1to 1000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 2 times per day. The dosages,however, may be varied depending upon the requirement of the patients,the severity of the condition being treated and the compound beingemployed. The use of either daily administration or post-periodic dosingmay be employed. Preferably these compositions are in unit dosage formssuch as tablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient oringredients are mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of one ormore glucose reabsorption inhibitors and one or more antidiabeticagents, or a pharmaceutically acceptable salt thereof. When referring tothese preformulation compositions as homogeneous, it is meant that theactive ingredient or ingredients are dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient or ingredients of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of material can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also include thesynthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

Advantageously, the combinations of one or more glucose reabsorptioninhibitors of the present invention, alone or in combination with one ormore additional antidiabetic agents, may be administered in a singledaily dose, or the total daily dosage may be administered in divideddoses of two, three or four times daily. Furthermore, one or moreglucose reabsorption inhibitors and/or one or more antidiabetic agentsaccording to the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalskin patches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

Wherein the present invention is directed to the administration of acombination, the compounds may be co-administered simultaneously,sequentially, or in a single pharmaceutical composition. Where thecompounds are administered separately, the number of dosages of eachcompound given per day, may not necessarily be the same, e.g. where onecompound may have a greater duration of activity, and will therefore, beadministered less frequently.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, thestrength of the preparation, the mode of administration, and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient age,weight, diet and time of administration, will result in the need toadjust dosages.

The novel compositions of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of lipids, including but notlimited to amphipathic lipids such as phosphatidylcholines,sphingomyelins, phosphatidylethanolamines, phophatidylcholines,cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidicacids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyldimethylammonium propanes, and stearylamine, neutral lipids such astriglycerides, and combinations thereof. They may either containcholesterol or may be cholesterol-free.

From Formula (IV) and other disclosed formulae it is evident that somecompounds in the compositions of the invention may have one or moreasymmetric carbon atoms in their structure. It is intended that thepresent invention include within its scope the stereochemically pureisomeric forms of the compounds as well as their racemates.Stereochemically pure isomeric forms may be obtained by the applicationof art known principles. Diastereoisomers may be separated by physicalseparation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereospecificreactions.

Some compounds in the compositions of the present invention may havevarious individual isomers, such as trans and cis, and various alpha andbeta attachments (below and above the plane of the drawing). Inaddition, where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared as a single stereoisomeror in racemic form as a mixture of some possible stereoisomers. Thenon-racemic forms may be obtained by either synthesis or resolution. Thecompounds may, for example, be resolved into their componentsenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation. The compounds may also beresolved by covalent linkage to a chiral auxiliary, followed bychromatographic separation and/or crystallographic separation, andremoval of the chiral auxiliary. Alternatively, the compounds may beresolved using chiral chromatography. Unless otherwise noted, the scopeof the present invention is intended to cover all such isomers orstereoisomers per se, as well as mixtures of cis and trans isomers,mixtures of diastereomers and racemic mixtures of enantiomers (opticalisomers) as well.

The therapeutic effect of the glucose reabsorption inhibitoradministered in combination with one or more antidiabetic agent(s) intreating diabetes, Syndrome X, or associated symptoms or complicationscan be shown by methods known in the art. The following examples ofcombination treatment with SGLT inhibitors and other antidiabetic agentssuch as RXR modulators are intended to illustrate the invention but notto limit it.

G. SYNTHETIC CHEMICAL EXAMPLES

One aspect of the invention features compounds of formula (IV) asdescribed above in the Summary section, the description, and theappended claims. These disclosed compounds may be made according totraditional synthetic organic chemistry methods or according to matrixor combinatorial chemistry methods. The Schemes and Examples 1-9 belowprovide general guidance and detailed examples of how the disclosedcompounds may be prepared.

¹HNMR spectra were measured on a Brucker AC-300 (300 MHz) spectrometerusing tetramethylsilane (TMS) as an internal standard.

Example 1 3-(4-Ethylbenzyl)-5-(β-D-glucopyranosyl)-1H-indole

A. 5-Bromo-3-formyl-indole-1-carboxylic acid diethylamide: To asuspension of sodium hydride (0.93 g, 37 mmol) in anhydrous THF (75 mL)was added dropwise a solution of 5-bromo-1H-indole-3-carbaldehyde (7.5g, 34 mmol) in anhydrous THF (60 ml) at 0° C. After stirring at 0° C.for 15 min, N,N-diethylcarbamyl chloride (5.0 g, 37 mmol) was addeddropwise into the reaction mixture. The mixture was warmed to roomtemperature and stirred overnight. The reaction was then quenched withwater and extracted with ethyl acetate. The organics were washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was crystallized from ether/hexane to give the titlecompound (8.75 g, 80%) as a white solid.

B. 5-Bromo-3-(4-ethyl-benzyl)-indole-1-carboxylic acid diethylamide: Toa solution of Part A (3.3 g, 10 mmol) in 20 mL of anhydrous THF wasadded dropwise a 0.5 M solution of 4-ethylphenylmagnesium bromide inanhydrous THF (22 mL, 11 mmol) at 0° C. The reaction mixture wascontinued stirring at 0° C. for 30 min, quenched with a saturatedammonium chloride solution and extracted with ethyl acetate. The organicextracts were dried over sodium sulfate and concentrated in vacuo. Thecrude product was used directly in the next step.

To a solution of the crude indolecarbinol in 20 mL of dichloromethanewas added triethylsilane (1.16 g, 10.0 mmol) at −78° C., followed byaddition of a 1.0 M solution of stannic chloride in dichloromethane (20mL, 20 mmol). The reaction mixture was continued stirring at −78° C. for20 min, quenched with water and warmed to room temperature. Afterextraction with dichloromethane, the organic extracts were dried oversodium sulfate, concentrated in vacuo and chromatographed with silicagel eluting with ethyl acetate/hexane (10:100) to provide the titledcompound (3.4 g, yield: 82%) as a white solid.

C. 5-Bromo-3-(4-ethyl-benzyl)-1H-indole: The compound prepared in Part B(3.4 g, 8.2 mmol) was dissolved in ethanol (60 mL) and 25% aqueoussodium hydroxide (20 mL) and the resulting solution was brought toreflux for 3 h. After cooling to room temperature, the mixture wasdiluted with water (60 mL), concentrated in vacuo to remove most ofethanol, and extracted with ethyl acetate. The organic extracts werewashed with water and brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel eluting with ethyl acetate/hexane (1:4) to provide thetitle compound (2.0 g, 79%) as white needle crystals.

D. 5-Bromo-1-(tert-butyl-dimethyl-silanyl)-3-(4-ethyl-benzyl)-1H-indole:

To a suspension of sodium hydride (0.12 g, 4.8 mmol) in anhydrous THF (2mL) was added dropwise a solution of the compound prepared in Part C(1.28 g, 4.0 mmol) in anhydrous THF (6 ml) at 0° C. After stirring at 0°C. for 30 min, a 1.0M solution of tert-butyl-chloro-dimethyl-silane inanhydrous THF (4.5 mL, 4.5 mmol) was added dropwise into the reactionmixture. The mixture was warmed to room temperature and stirredovernight. The reaction was then quenched with water and extracted withethyl acetate. The organics were washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. The crude product was purifiedby chromatography on silica gel eluting with ethyl acetate/hexane(0.5:100) to provide the title compound (1.75 g, 100%) as a light yellowoil.

E.3-(4-Ethylbenzyl)-5-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(tert-butyl-dimethyl-silanyl)-1H-indole:To a stired solution of the compound prepared in Part D (1.75 g, 4.0mmol) in dry THF (2 mL) at −78° C. was added a 1.7 M solution oftert-butyl lithium in heptane (4.7 mL, 8.0 mmol) over a period of 15min. After stirring 30 min, a solution of2,3,4,6-tetra-O-benzyl-β-D-glucolactone (4.3 g, 8.0 mmol; prepared asdescribed by Benhaddou, R.; Carbohydrate Research 1994, 260, 243-250) indry THF (10 mL) was added at −78° C. over a period of 15 min. Thereaction mixture was stirred at −78° C. for 1 hr (reaction progress wasmonitored by TLC). Upon completion the reaction mixture was quenchedwith saturated aqueous NH₄Cl (5 mL), warmed to room temperature and thereaction mixture was diluted with ethyl acetate. The organic extractswere washed with water and brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude product was purified bychromatography on silica gel eluting with ethyl acetate/hexane (1:4) toprovide a mixture of the desired lactol and unreacted2,3,4,6-tetra-O-benzyl-β-D-glucolactone (2.8 g, ˜50% of the desiredlactol) as a light brown oil. This mixture was used directly to the nextstep without further purification.

To a solution of the above mixture (2.8 g) in dichloromethane (20 mL)was added triethylsilane (0.5 mL, 3.2 mmol) at −30° C., followed by theaddition of trifluoroborane diethyl ether (0.2 mL, 1.6 mmol). Aftersiring between −30 to −20° C. for 1 hr, when TLC analysis indicated thereaction was completed, the reaction was quenched by addition ofsaturated aqueous NaHCO₃ (3 mL). The mixture was warmed to roomtemperature and stirred for 1 hr. The reaction mixture was extractedwith ethyl acetate. The organic extracts were washed with water andbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The crude product was purified by chromatography on silica gel elutingwith ethyl acetate/hexane (1:4) to provide the title compound (0.68 g,19% for two steps) as a yellow oil.

F.3-(4-Ethylbenzyl)-5-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-indole:Part E (0.68 g, 0.78 mmol) was dissolved in THF (15 mL) and 25% aqueoussodium hydroxide (5 mL) and the resulting solution was brought to refluxfor 3 h. After cooling to room temperature, the mixture was diluted withwater (30 mL), and extracted with ethyl acetate. The organic extractswere washed with water and brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude product was purified bychromatography on silica gel eluting with ethyl acetate/hexane (1:3) toprovide the title compound (0.5 g, 85%) as white solid.

G. 3-(4-Ethylbenzyl)-5-(β-D-glucopyranosyl)-1H-indole: A solution ofPart F (0.30 g, 0.4 mmol) in ethanol (10 mL) and ethyl acetate (20 mL)was hydrogenated over 10% Pearlman's catalyst (0.30 g) under 14 psi ofH₂ for 40 h. The catalyst was removed by filtration and the filtrate wasconcentrated in vacuo. The crude product was purified by chromatographyon silica gel eluting with methanol/chloroform (10:100) to provide thetitled compound (0.04 g, 25%) as a white solid. ¹HNMR (300 MHz, CD₃OD) δ7.51 (s, 1H), 7.32 (d, J=8.52 Hz, 1H), 7.19-7.15 (m, 3H), 7.06 (d,J=7.87 Hz, 2H), 6.95 (s, 1H), 4.18-4.15 (m, 1H), 4.04 (s, 2H), 3.87 (d;J=12.2 Hz, 1H), 3.71-3.65 (m, 1H), 3.53-3.48 (m, 2H), 3.45-3.41 (m, 2H),2.58 (q, J=7.58 Hz, 2H), 1.19 (t, J=7.65 Hz, 3H). MS: m/z (M+Na) 420.

Example 2 5-(β-D-Glucopyranosyl)-3-(4-methoxybenzyl)-1H-indole

The title compound was prepared as a white solid, from5-bromo-3-formyl-indole-1-carboxylic acid diethylamide (Example 1, PartA) and 4-methoxyphenyl-magnesium bromide by the same procedure asdescribed in Example 1, Part B to G). ¹HNMR (300 MHz, CD₃OD) δ 7.49 (s,1H), 7.32 (d, J=8.20 Hz, 1H), 7.19-7.15 (m, 3H), 6.95 (s, 1H), 6.79 (d,J=8.55 Hz, 2H), 4.18-4.15 (m, 1H), 4.02 (s, 2H), 3.88-3.85 (m, 1H), 3.74(s, 3H), 3.70-3.66 (m, 1H), 3.50-3.48 (m, 2H), 3.42-3.35 (m, 2H). MS:m/z (M+Na) 422.

Example 3 5-(β-D-Glucopyranosyl)-3-[2-(4-methoxyphenyl)-ethyl]-1H-indole

A. 5-Bromo-3-[2-(4-methoxy-phenyl)-ethyl]-indole-1-carboxylic aciddiethylamide: To a solution of 4-methoxybenzyl triphenyphosphoniumchloride (7.5 g, 18 mmol) in anhydrous THF (75 mL) at −78° C. was addedLDA (9.0 mL, 18 mmol) and the resulting reaction mixture was allowed tostir at −78° C. for 1 h. Thereafter,5-bromo-3-formyl-indole-1-carboxylic acid diethylamide (1.9 g, 6 mmol,Example 1, Part A) was added and the resulting reaction mixture wasallowed to stir at −78° C. for 1 h and then warmed to room temperatureto stir overnight. The reaction mixture was poured onto 1N HCl solutionand extracted with ethyl acetate. The combined ethyl acetate extractswere washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel eluting with ethyl acetate/hexane (1:4) to provide themixture of alkenes (2.3 g, 90%, E:Z ˜1:1) as a brown oil. A solution ofthe above alkenes (2.3 g, 5.4 mmol) in dichloromethane (100 mL) washydrogenated over Adam's catalyst (300 mg) under H₂ (15 psi) for 2 h.The catalyst was removed by filtration and the filtrate was concentratedin vacuo. The crude product was purified by chromatography on silica geleluting with ethyl acetate/hexane (1:4) to provide the title compound(1.43 g, 62%) as a colorless oil.

B. 5-Bromo-3-[2-(4-methoxy-phenyl)-ethyl]-1H-indole:Part B (1.43 g, 3.3mmol) was dissolved in ethanol (30 mL) and 25% aqueous sodium hydroxide(10 mL) and the resulting solution was brought to reflux for 3 h. Aftercooling to room temperature, the mixture was diluted with water (30 mL),concentrated in vacuo to remove most of ethanol, and extracted withethyl acetate. The organic extracts were washed with water and brine,dried over anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct was purified by chromatography on silica gel eluting with ethylacetate/hexane (1:4) to provide the title compound (1.0 g, 91%) as alight brown oil.

C.5-Bromo-1-(tert-butyl-dimethyl-silanyl)-3-[2-(4-methoxy-phenyl)-ethyl]-1H-indole:To a suspension of sodium hydride (0.081 g, 4.0 mmol) in anhydrous THF(2 mL) was added dropwise a solution of Part C (0.85 g, 2.7 mmol) inanhydrous THF (3 ml) at 0° C. After stirring at 0° C. for 30 min, a 1.0M solution of tert-butyl-chloro-dimethyl-silane in anhydrous THF (3.2mL, 3.2 mmol) was added dropwise into the reaction mixture. The mixturewas warmed to room temperature and stirred overnight. The reaction wasthen quenched with water and extracted with ethyl acetate. The organicswere washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel eluting with ethyl acetate/hexane (0.5:100) to provide thetitle compound (0.92 g, 79%) as a light yellow oil.

D. 5-(β-D-Glucopyranosyl)-3-[2-(4-methoxyphenyl)-ethyl]-1H-indole:

The title compound was prepared as a white solid, from Part C by thesame procedure as described in Example 1, Part E, F and G. ¹HNMR (300MHz, CD₃OD) δ 7.58 (s, 1H), 7.31 (d, J=8.06 Hz, 1H), 7.18 (dd, J=8.39,1.59 Hz, 1H), 7.10 (dd, J=6.63, 2.16 Hz, 2H), 6.92 (s, 1H), 6.81-6.78(m, 2H), 4.21 (d, J=8.99 Hz, 1H), 3.91-3.87 (m, 1H), 3.75 (s, 3H),3.73-3.69 (m, 1H), 3.54-3.51 (m, 2H), 3.49-3.45 (m, 2H), 3.00-2.98 (m,2H), 2.94-2.90 (m, 2H). MS: m/z (M+Na) 436.

Example 4 3-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-1H-indole

A. (4-Bromo-1H-indol-3-yl)-(4-ethyl-phenyl)-methanone: To a suspensionof AlCl₃ (3.0 g, 22.5 mmol) in dichloromethane (50 mL) was added asolution of 4-bromoindole (2.21 g, 11.3 mmol) in dichloromethane (25 mL)at room temperature over the period of 20 mins, followed by the additionof a solution of 4-ethyl-benzoyl chloride (2.5 mL, 17 mmol) indichloromethane (25 mL) over the period of 20 mins. The resultingsolution was stirred at room temperature overnight, and saturated sodiumbicarbonate solution was added in a water-ice bath to quench thereaction. The aqueous layer was extracted with dichloromethane. Theorganics were washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product was triturated in diethyl etherto obtain the title compound (1.8 g, 48%) as white solids.

B. (1-Benzenesulfonyl-4-bromo-1H-indol-3-yl)-(4-ethyl-phenyl)-methanone:

A mixture of a compound prepared from Part A (1.6 g, 5 mmol),tetrabutylammonium bromide (0.16 g, 0.5 mmol) and benzenesulfonylchloride (1.3 g, 7.5 mmol) in 25% aqueous sodium hydroxide (10 mL) andbenzene (50 mL) was stirred at room temperature overnight. The reactionmixture was quenched by addition of water and extracted with ethylacetate. The organic layer was washed with water and brine, dried overanhydrous sodium sulfate and concentrated in vacuo and chromatographedon silica gel eluting with ethyl acetate/hexane (30:100) to give thetitle compound (1.80 g, 76%).

C. 1-Benzenesulfonyl-4-bromo-3-(4-ethyl-benzyl)-1H-indole: To asuspended AlCl₃ (0.8 g, 6 mmol) in dichloromethane (10 mL) was addedborane-tert-butylamine complex (0.52 g, 6 mmol) at 0° C. The resultingmixture was stirred at 0° C. for 10 mins followed by addition of asolution of a compound from Part B (0.94 g, 2 mmol) in dichloromethane(15 mL). The reaction mixture was stirred at room temperature overnight,and NaOH (3M, 20 mL0 was added with crushed ice to quench the reaction.The basic aqueous layer was extracted with dichloromethane. The organicswere washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude product (0.90 g, 99%) was pure enoughfor the next step without further purification.

D. 4-Bromo-3-(4-ethyl-benzyl)-1H-indole: Part C (0.90 g, 2 mmol) wasdissolved in 1:1 mixture of ethanol and THF (20 mL) with 50% aqueoussodium hydroxide (2 mL). The resulting solution was brought to refluxfor 3 h. After cooling to room temperature, the mixture was diluted withwater (20 mL), concentrated in vacuo to remove most of ethanol, andextracted with ethyl acetate. The organic extracts were washed withwater and brine, dried over anhydrous sodium sulfate and concentrated invacuo. The crude product was purified by chromatography on silica geleluting with ethyl acetate/hexane (30:100) to give the title compound(0.53 g, 84%) as a colorless oil.

E. 3-(4-Ethylbenzyl)-4-(β-D-glucopyranosyl)-1H-indole: The titlecompound was prepared as a white solid, from Part D by the sameprocedure as described in Example 1, Part D, E, F and G. ¹HNMR (300 MHz,CD₃OD) δ 7.33 (dd, J=7.42, 1.64 Hz, 1H), 7.18 (d, J=1.79 Hz, 1H),7.16-7.07 (m, 5H), 6.90 (s, 1H), 4.72 (d, J=9.64 Hz, 1H), 4.35 (d,J=16.5 Hz, 1H), 4.26 (d, J=16.4, 1H), 3.69-3.52 (m, 3H), 3.44-3.39 (m,2H), 2.95 (s, 1H), 2.58 (q, J=7.58 Hz, 2H), 1.19 (t, J=7.65 Hz, 3H). MS:m/z (M+Na) 420.

H. BIOLOGICAL EXAMPLES Example 1 Materials and Methods

Cloning of the human SGLT1 and human SGLT2 cDNAs and construction of themammalian expression vector: The human SGLT1 cDNA (Genbank M24847) wascloned from human small intestine. Human SGLT2 cDNA (Genbank M95549) wascloned from human kidney. Both full cDNAs were subcloned into pcDNA andsequenced to verify the integrity of the construct.

Generation of CHO-K1 cells stably expressing human SGLT1 or human SGLT2:Transfection of CHO-K1 cells was performed using DMRIE-C reagent (LifeTechnologies, Gaithersburg, Md.). Transfectants were then selected inthe presence of the antibiotic G418 (Gibco-BRL, Grand Island, N.Y.) at400 μg/ml. Individual clones were then characterized using thefunctional assay described below.

Cell-based assay for sodium-dependent glucose transport: Cell linesstably expressing human SGLT1 or SGLT2 were then used for functionalanalysis of Na⁺-dependent glucose uptake. Briefly, cells were plated ata density of 65,000 cells per well in a 96-well plate and allowed togrow for 48 hours. Cells were subsequently washed one time with AssayBuffer (50 mM HEPES pH 7.4, 20 mM Tris, 5 mM KCl, 1 mM MgCl₂, 1 mM CaCl₂and 137 mM NaCl) and treated with compound in the absence or presence ofNaCl for 15 minutes. Cells were then labeled with¹⁴C-α-methylglucopyranoside (AMG, Sigma, St. Louis, Mo.) anon-metabolizable glucose analog specific for sodium-dependent glucosetransporters as previously described (Peng, H. and Lever J. E.Post-transcriptional regulation of Na⁺/glucose cotransporter (SGLT1)gene expression in LLC-PK1 cells. J Biol Chem 1995; 270:20536-20542.).After 2 hours the labelled cells were washed three times with ice-coldPBS. After aspiration, cells were solubilized using Microscint 20(Packard, Meriden, Conn.) and Na-dependent ¹⁴C-AMG uptake was quantifiedby measuring radioactivity. Plates were counted in a TopCount (Packard,Meriden, Conn.). Results are reported as the % inhibition or IC50 valuefrom a representative experiment. Variability for the functional assaywas typically within 20%. TABLE 3 CHOK-SGLT2 CHOK-SGLT1 Example # IC50(uM) IC50 (uM) 4 12% Inh at 10 uM inactive 3 60% Inh at 10 uM inactive 21.395 ± 0.067 inactive 1 0.132 ± 0.024 inactive

Example 2 In Vivo Assay for Efficacy

Male Zucker Diabetic Fatty (ZDF) rats (7-8 weeks) were obtained fromCharles River. Animals were maintained on a 12-hour light/dark cycle ina temperature-controlled room. Animals were given ad libitum access tofood (standard rodent diet Purina 5008) and water. Animals were fastedfor 12 hours prior to initiation of the experiment. On the morning ofthe experiment, animals were administered vehicle (0.5% methylcellulose)or compound by oral gavage (1 ml/kg). After one hour, animals receivedan oral glucose challenge (4 ml/kg of 50% solution) and were immediatelyplaced in metabolism cages. Animals were given free access to water andurine was collected for 4 hours. Urinary glucose was quantified usingthe Trinder Reagent (Sigma).

Example 3 Effects on Plasma Glucose, Plasma Insulin, PlasmaTriglycerides, Plasma Free Fatty Acids, Liver Weight, and Body Weight

To examine the effect of an SGLT inhibitor in combination with an RXRagonist, female db/db mice (6-7 weeks of age/Jackson Labs, ME) aretreated daily for 11 days with vehicle (0.5% methylcellulose), an RXRagonist (0.1-10 mpk (mg/kg)), an SGLT inhibitor (100 mpk), or an RXRagonist plus SGLT inhibitor. Mice (n=8 animals/group) receive the testcompounds or vehicle by oral gavage in a volume of 10 ml/kg of bodyweight. Body weight is recorded on day 1, prior to dosing, and days 4, 8and 11. Eighteen hours after the final dose, mice are weighed andanesthetized with CO₂/O₂ (70:30). Mice are then bled by retro-orbitalsinus puncture into 2 mL heparinized polypropylene tubes on ice. Plasmasamples are then assayed for glucose, insulin, triglycerides, and freefatty acids. Livers are excised, weighed and frozen.

The SGLT inhibitors and RXR agonists have distinct mechanisms of action.Improved glycemic control, measured as a decrease in plasma glucose,plasma insulin, plasma free fatty acids, or plasma triglycerides, or acombination thereof, can be observed at lower concentrations of an RXRagonist when given in combination with an SGLT inhibitor. Therefore, aleftward shift in the dose-response curve for effect of an RXR agoniston the above parameters can become apparent. In addition, the weightgain observed following treatment with RXR agonists is less pronouncedwhen given with the SGLT inhibitor, since SGLT inhibitors' promotion ofthe urinary excretion of glucose and loss of calories from the body isdemonstrated by reduction in weight or weight gain. Also, since SGLTinhibitors promote a mild diuresis, the edema (and the edematous weightgain) commonly observed after treatment with RXR agonists can be lesspronounced or absent. A reduction in the amount of an RXR agonist suchas MX-6054 necessary to achieve efficacy in turn improves theside-effect profile. The decreased side effects can include suchconditions as fatty liver, increased liver weight, body weight gain,heart weight gain, edema, cardiac hypertrophy, hepatohypertrophy,hypoglycemia, and hepatotoxicity, or any combination thereof.

Example 4 Effects on Plasma Glucose, HbA1c, Hematocrit, Plasma Insulin,Plasma Triglycerides, Plasma Free Fatty Acids, Total Cholesterol, HDL,Plasma Drug Levels, Liver Weight, Heart Weight, Fat Content and BodyWeight

To examine the effect of an SGLT inhibitor in combination with an RXRagonist, male ZDF rats (6 weeks of age/GMI) are treated daily for 28days with vehicle (0.5% methylcellulose), an RXR agonist (0.1 mpk-10mpk), SGLT inhibitor (3-100 mpk), or an RXR agonist plus SGLT inhibitor.Rats (n=8 animals/group) receive the test compounds or vehicle by oralgavage in a volume of 2 ml/kg of body weight. Body weight is recorded onday 1, prior to dosing, and twice a week for the duration of the study.On the day prior to the final dose, animals are fasted overnight. Onehour after the final dose, rats are weighed and anesthetized with CO₂/O₂(70:30). Rats are then bled by retro-orbital sinus puncture into 2 mLheparinized polypropylene tubes on ice. Rats then receive a glucosechallenge (2 g/kg p.o) and are placed in metabolism cages for the urinecollection (4 hours). Animals are then sacrificed and epididymal fatpads, livers, and hearts are excised, weighed and frozen forhistological examination. Plasma samples are then assayed for glucose,HbA1c, insulin, hematocrit, plasma drug levels, total cholesterol, HDL,free fatty acids, and triglycerides. Urine volume and urinary glucose,protein, osmolarity, electrolytes (Na, K, Cl), BUN and creatinine aremeasured.

The SGLT inhibitors and RXR agonists have distinct mechanisms of action.Improved glycemic control, measured as a decrease in plasma glucose,HbA1c, plasma insulin, or plasma triglycerides, or a combinationthereof, can be observed at lower concentrations of RXR agonists whengiven in combination with an SGLT inhibitor. Therefore, a leftward shiftin the dose-response curve for effect of RXR agonists on the aboveparameters can become apparent. In addition, the weight gain observedfollowing treatment with RXR agonists is less pronounced when given withthe SGLT inhibitor, since SGLT inhibitors' promotion of the urinaryexcretion of glucose and loss of calories from the body is demonstratedby reduction in weight or weight gain. Also, since SGLT inhibitorspromote a mild diuresis, the edema (and the edematous weight gain)commonly observed after treatment with RXR agonists can be lesspronounced or absent. This can be demonstrated by a reduction in the RXRagonist-induced increase in heart weight. A reduction in the amount ofRXR agonists necessary to achieve efficacy in turn improves theside-effect profile. The decreased side effects can include suchconditions as fatty liver, increased liver weight, body weight gain,heart weight gain, edema, cardiac hypertrophy, hepatohypertrophy,hypoglycemia, and hepatotoxicity, or any combination thereof.

The above examples can also show that the oral administration of an SGLTinhibitor in combination with an antidiabetic agents, such as an RXRmodulator, improve the status of other markers of diabetes mellitusincluding glycosylated hemoglobin (Hgb A1C) levels. Particularly, theoral administration of an SGLT inhibitor in combination with one or moreRXR modulators can reduce body weight or body weight gain as well asliver weight or liver weight gain, compared to administration of one ormore RXR modulators alone.

Thus, for treating diabetes, particularly Type II diabetes mellitus, orSyndrome X, a compound of Formula (IV) in combination with one or moreantidiabetic agents, such as an RXR agonist that increases insulinsensitivity, may be employed comprising administering repeated oraldoses of the compound of Formula (IV) in the range of about 25 to 1000mg once or twice daily and repeated doses of the anti-diabetic agent oragents at jointly effective dosages. The jointly effective dosage forantidiabetic agents disclosed herein may be readily determined by thoseskilled in the art based on standard dosage guidelines. In particular,such combined administration can be effective to accomplish reduction ofbody weight, body weight gain, liver weight, or liver weight gain in thesubject.

Additionally, a method comprising (a) administering to a subject ajointly effective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of anantidiabetic agent such as an RXR modulator can be used to reduce bodyweight, body weight gain, or liver weight of the subject in needthereof, wherein the combined administration can be in any order and thecombined jointly effective amounts provide the desired therapeuticeffect.

Also, a method comprising (a) administering to a subject a jointlyeffective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of anantidiabetic agent can be used to control body weight, body weight gain,liver weight, or liver weight gain of the subject having diabetes,Syndrome X, or associated symptoms or complications, wherein thecombined administration can be in any order and the combined jointlyeffective amounts providing the desired therapeutic effect.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient's sex, age,weight, diet, time of administration and concomitant diseases, willresult in the need to adjust dosages.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1-22. (canceled)
 23. A method for treating diabetes in a mammal, saidmethod comprising administering to a mammal in need of treatment aneffective amount of a pharmaceutical composition of claim
 21. 24. Amethod of claim 23, wherein said diabetes is type II diabetes.
 25. Amethod for lowering serum glucose in a mammal, said method comprisingadministering to a mammal in need of treatment an effective amount of apharmaceutical composition of claim
 21. 26. A method for treatingimpaired glucose tolerance in a mammal, said method comprisingadministering to a mammal in need of treatment an effective amount of apharmaceutical composition of claim
 21. 27. A method for treating orinhibiting impaired glucose tolerance in a mammal, said methodcomprising administering to a mammal in need of treatment an effectiveamount of a pharmaceutical composition of claim
 21. 28. A method forreducing the body mass index, body weight, or percentage body fat in amammal, said method comprising administering to a mammal in need oftreatment an effective amount of a pharmaceutical composition of claim21.
 29. A method of claim 28, wherein said reduction of body mass indexis a method for treating obesity or an overweight condition.
 30. Amethod for inhibiting the sodium glucose transporter in a cell, byexposing said cell to a compound of claim 1 or a metabolite thereof. 31.A method for treating diabetes or Syndrome X, or associated symptoms orcomplications thereof in a subject, comprising administering to saidsubject a jointly effective amount of a glucose reabsorption inhibitorof formula (IV); and administering to said subject a jointly effectiveamount of a second antidiabetic agent, said co-administration being inany order and the combined jointly effective amounts providing thedesired therapeutic effect.
 32. The method of claim 31, wherein thesecond antidiabetic agent is an RXR agonist.
 33. The method of claim 31,wherein the diabetes or Syndrome X, or associated symptoms orcomplications thereof is selected from IDDM, NIDDM, IGT, IFG, obesity,nephropathy, neuropathy, retinopathy, atherosclerosis, polycysticovarian syndrome, hypertension, ischemia, stroke, heart disease,irritable bowel disorder, inflammation, and cataracts.
 34. The method ofclaim 31 wherein the diabetes or Syndrome X, or associated symptoms orcomplication thereof is IDDM.
 35. The method of claim 31, wherein thediabetes or Syndrome X, or associated symptoms or complications thereofis NIDDM.
 36. The method of claim 31, wherein the diabetes or SyndromeX, or associated symptoms or complications thereof is IGT or IFG. 37.The method of claim 31, further comprising administering to said subjecta jointly effective amount of a third antidiabetic agent.
 38. The methodof claim 37, wherein the third antidiabetic agent is selected from (aa)insulins, (bb) insulin analogues; (cc) insulin secretion modulators, and(dd) insulin secretagogues.
 39. The method of claim 31, wherein theglucose reabsorption inhibitor is an SGLT inhibitor.
 40. The method ofclaim 31, wherein the glucose reabsorption inhibitor is an SGLT1inhibitor.
 41. The method of claim 31, wherein the glucose reabsorptioninhibitor is an SGLT2 inhibitor.
 42. The method of claim 31, wherein theglucose reabsorption inhibitor is a compound of Formula (IV) or anoptical isomer, enantiomer, diastereomer, racemate or racemic mixturethereof, ester, prodrug form, or a pharmaceutically acceptable saltthereof.
 43. The method of claim 31, wherein the jointly effectiveamount of an SGLT inhibitor is from about 10 to 1000 mg.
 44. The methodof claim 31, wherein the jointly effective amount of an SGLT inhibitoris an amount sufficient to reduce the plasma glucose excursion followinga meal.
 45. A method for inhibiting the onset of diabetes or Syndrome X,or associated symptoms or complications thereof in a subject, saidmethod comprising
 46. (a) administering to said subject a jointlyeffective amount of a glucose reabsorption inhibitor of formula (IV);and (b) administering to said subject a jointly effective amount of asecond antidiabetic agent, said co-administration being in any order andthe combined jointly effective amounts providing the desiredprophylactic effect.
 46. The method of claim 45, wherein said onset isfrom pre-diabetic state to NIDDM.
 47. A pharmaceutical compositioncomprising a glucose reabsorption inhibitor of formula (IV), a secondantidiabetic agent, and a pharmaceutically acceptable carrier.
 48. Thepharmaceutical composition of claim 45, 46, or 47, wherein the glucosereabsorption inhibitor is an SGLT inhibitor.
 49. The pharmaceuticalcomposition of claim 45, wherein the glucose reabsorption inhibitor isan SGLT1 inhibitor.
 50. The pharmaceutical composition of claim 45,wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor.
 51. Aprocess for formulating a pharmaceutical composition, comprisingformulating together a glucose reabsorption inhibitor, a secondantidiabetic agent, and a pharmaceutically acceptable carrier.
 52. Aprocess for making a pharmaceutical composition comprising mixing one ormore glucose reabsorption inhibitors in combination with a secondantidiabetic agent for the preparation of a medicament for treating acondition selected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy,neuropathy, retinopathy, atherosclerosis, polycystic ovarian syndrome,hypertension, ischemia, stroke, heart disease, irritable bowel disorder,inflammation, and cataracts.
 53. A method for inhibiting the progressionof a prediabetic condition in a subject to a diabetic condition,comprising (a) administering to said subject a jointly effective amountof a glucose reabsorption inhibitor of formula (IV); and (b)administering to said subject a jointly effective amount of an seconddiabetic agent, said co-administration being in any order and thecombined jointly effective amounts providing the desired inhibitingeffect.
 54. The method of claim 53 wherein said condition is IGT or IFG.55. The method of claim 53 wherein said inhibiting of the progression ofa prediabetic condition is prevention of the progression of theprediabetic condition to a diabetic condition.
 56. The method of claim53, wherein the glucose reabsorption inhibitor is a compound of formula(IV), optionally having one or more hydroxyl or diol protecting groups,or an optical isomer, enantiomer, diastereomer, racemate or racemicmixture, ester, prodrug form, or a pharmaceutically acceptable saltthereof